1. Field of Endeavor
The present invention relates to diagnosis and more particularly to diagnosis and assessment of skeletal related disease using calcium 41.
2. State of Technology
Skeletal complications of cancer cause significant health problems because certain tumors commonly metastasize to bone, including myeloma, breast, lung, prostate, kidney, thyroid, melanoma, and lymphomas. For these patients, skeletal complications such as intractable bone pain, pathologic fractures, nerve compression syndromes, and hypercalcemia signal that the malignant process is incurable (Mundy G R. Mechanisms of bone metastasis. Cancer. 1997; 80:1546-56). Cancer cells reaching the bone microenvironment hijack normal cellular function by producing bioactive factors and peptides, leading to osteosclerotic lesions and/or osteolytic bone destruction (Deftos L J. Prostate carcinoma: production of bioactive factors. Cancer. 2000; 88:3002-8). Accelerated bone turnover locally releases high concentrations of bone-derived growth factors, further promoting tumor growth in a vicious cycle (Mundy G R. Mechanisms of bone metastasis. Cancer. 1997; 80:1546-56).
The need for early detection and improved management of metastatic bone disease has driven the search for new markers of skeletal tumor burden, disease progression, and response to treatment (Vinholes J, Coleman R, Eastell R. Effects of bone metastases on bone metabolism: implications for diagnosis, imaging and assessment of response to cancer treatment Cancer Treat Rev. 1996; 22:298-331). Urinary and serum biomarkers of bone turnover, such as bone specific alkaline phosphatase and Type I collagen fragments, have proven useful in research populations (Coleman R E. The clinical use of bone resorption markers in patients with malignant bone disease. Cancer. 2002; 94:2521-33.), and may aid in directing treatment when greatly elevated (Brown J E, Cook R J, Major P, et al. Bone turnover markers as predictors of skeletal complications in prostate cancer, lung cancer, and other solid tumors. J Natl Cancer Inst. 2005; 97(459-69).
However, the ultimate value of these techniques for individual patients is uncertain, due (in part) to high natural variability of biomarkers in urine and serum (Kannis J A, McCloskey E V. Bone turnover and biochemical markers in malignancy. Cancer. 1997; 80:1538-45). Applicants believe that labeling the human skeleton with a 41Ca tracer and monitoring urinary tracer abundance will provide a non-invasive, highly sensitive, clinically useful measure of bone turnover. The longest half-life isotope of calcium, 41Ca, provides a sensitive method for tracking short and long-term bone turnover parameters. Due to extremely low natural abundance (<10−15), a single sub-physiological 41Ca dose (less than 1 ug=4 kBq=0.1 uCi) remains quantifiable via accelerator mass spectrometry (AMS) in blood and urine for many years: this longevity within the body's primary calcium pool makes 41Ca variation specific to bone turnover (Weaver C M. Use of calcium tracers and biomarkers to determine calcium kinetics and bone turnover. Bone. 1998; 22(5):103S-104S). The long half-life (100,000 years) and low energy decay mode (pure electron capture) make 41Ca uniquely benign: lifetime radioactive exposure from ingested or injected dose (<2e-10 and <7e-10 Sv/Bq, respectively) is smaller than ten seconds of a commercial airline flight (Friedberg W, Copeland K, Duke F E, O'Brien K III, Darden E B Jr. Radiation exposure during air travel: guidance provided by the federal aviation administration for air carrier crews. Health Phys. 2000; 79(5):591-595). Applicants demonstrate that urinary 41Ca/Ca in humans is very stable over time, and that a 41Ca assay may be sensitive enough to detect modulations in urinary 41Ca/Ca due to bone disruption and tumor proliferation from metastatic bone disease. Applicants also conducted two proof-of-concept studies using a human xenograft tumor model in nude mice. One establishing that 41Ca preferentially labels bone, and another tested Applicants' hypothesis that pre-labeled bones release 41Ca at a rate directly proportional to cancer cell proliferation and bone destruction during robust skeletal tumor growth.
The article “high-throughput measurement of 41Ca by accelerator mass spectrometry to quantitate small changes in individual human bone turnover rates,” by Darren J. Hillegonds, Robert Fitzgerald, David Herold, Yumei Lin, and John S. Vogel in the Journal of the Association for Laboratory Automation (JALA), Volume 9, Issue 3, Pages 99-102 (June 2004) provides the following state of technology information, “Biochemical markers of bone turnover suffer from large analytical and natural fluctuations (20-30%), making small differences in bone resorption impossible to resolve. This limits the clinical utility of such markers for individuals with the skeletal complications associated with many disease states (e.g., metastatic cancer, renal failure, osteoporosis).”
The article “41Ca and Accelerator Mass Spectrometry to Monitor Calcium Metabolism in End Stage Renal Disease Patients,” by Robert L. Fitzgerald, Darren J. Hillegonds, Douglas W. Burton, Terrance L. Griffin, Scott Mullaney, John S. Vogel, Leonard J. Deftos, and David A. Herold in Clinical Chemistry, 2005; 51(11): 2095-2102 provides the following state of technology information, “Monitoring bone resorption with measurements of bone density and biochemical markers is indirect,”